The focus of this research is to define the natural history of HPV infection and cervical neoplasia, particularly immunologic and other cofactors that explainwhy cervical HPV infection (a common sexually-transmitted diseases) progresses in rare instances to high-grade neoplasia. Accompanying prevention research on HPV diagnostics attempts to improve cervical cancer screening, while projectson HPV immunology are on the forefront of worldwide etiologic and preventive vaccine development efforts. Several methodologic and long-term projects were completed in FY 1999. Extremely high prospective relative risks of high-grade cervical intraepithelial neoplasia were observed to follow infection with cancer- associated HPV types, based on data from the Portland cohort study. Improved cytologic and HPV DNA test methods were validated during the enrollment phase of the Guanacaste cohort, a 10,000-womanrandom sample of a high-risk province of Costa Rica. Much of the natural history work in the next few years will derive from the follow-up data from this cohort. Serologic projects further demonstrated the HPV-type specificity of the new tests based on synthesized virus-like particles now available for major cancer-associated types. Methods research has also been completed on biomarkers of possible protective immunity to HPV infection that might be useful for the proposed Phase 3 prophylactic trial against HPV 16 infection. Prophylactic vaccination against HPV 16, the most important HPV type, is the central and most ambitious aspect of this project. The immunogenicity and safety of HPV 16 virus-like particles as antigens are being evaluated in collaborative Phase 1 and 2 trials at Johns Hopkins. Results to date are very promising. A full-scale Phase 3 randomized controlled trial of two candidate vaccines against placebo is tentatively scheduled to begin within about two years if the all work among U.S. women continues as hoped. Costa Rica was chosen for the Phase 3 trial because of our extensive successful scientific collaborations there, the continued high risk of cervical cancer, the universal medical system providing national linkage, and the likelihood of very high participation over many necessary years of close clinical follow-up. Over 10,000 women are scheduled to be vaccinated. - Human Subjects & Human Subjects: Interview, Questionaires, or Surveys Only & Human Tissues, Fluids, Cells, etc.